The first therapeutic use of corticosteroids was demonstrated in the 1950's with the introduction of cortisone acetate treatment for rheumatoid arthritis. Further studies demonstrated that the insertion of unsaturation into the 1,2 position of hydrocortisone and cortisone caused the resultant steroids, prednisolone and prednisone, to have enhanced potency and to cause less drug-induced salt retention. Subsequently, most other steroids used for the treatment of corticoid-responsive diseases have been synthesized so that they contain a double bond in the 1,2 position of the steroid molecule. In 1977, two U.S. patents were issued which represent new approaches to the synthesis of corticosteroids from sterol precursors. U.S. Pat. No. 4,035,236 covers a process for preparing 9.alpha.-hydroxyandrostenedione via fermentation of sitosterol, stigmasterol, or cholesterol. U.S. Pat. No. 4,041,055 discloses a general process for the synthesis of medically useful corticosteroids from this androstene. Intermediates covered in this chemisty can possess a 3-keto-.DELTA..sup.4,9(11) configuration.
Following are prior art methods which disclose the bioconversion of 1,2-saturated steroids to their corresponding 1,2-dehydro steroids:
U.S. Pat. No. 2,837,464 "Process for Production of Dienes by Corynebacterium". PA0 Description of 1-dehydrogenation of steroids in fermentation beers by Arthrobacter (Corynebacterium) simplex. PA0 U.S. Pat. No. 3,360,439 entitled "Process for Preparing 1-dehydro Steroids". PA0 Description of 1-dehydrogenation of steroids by use of A. simplex cells pretreated with a lower alkanol or lower alkanone such as acetone before mixing with the substrate and a hydrogen carrier. PA0 Charney, W. and Herzog, H. 1967. Microbial Transformation of Steroids. Academic Press, Inc., New York, pp 4-9, 236-261. PA0 Historical background on steroid bioconversions and taxonomic listing of microorganisms known to carry out 1-dehydrogenation. PA0 (1) androsta-4-ene-3,17-dione and PA0 androsta-4,9(11)-diene-3,17-dione and its 6.alpha.-fluoro, 6.alpha.-methyl, or 16-methyl derivatives. PA0 1. 17.alpha.-hydroxypregn-4-ene-20-yn-3-one and its 16-methyl derivatives; PA0 2. 11.beta., 21-dihydroxy-pregn-4,17(20)-diene-3-one and its 6.alpha.-methyl derivative; PA0 3. 20-chloro-pregn-4,9(11),17(20)-triene-21-al-3-one; PA0 4. several groups of 3,20-diketo-.DELTA..sup.4 -pregnenes, including
The prior art does not disclose or suggest the subject improved process.